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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2297.)
© 2000 American Heart Association, Inc.

Thrombosis

Role of the Angiotensin AT₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Hong-Chi Chen; Julie L. Bouchie; Alexandra S. Perez; Allen C. Clermont; Seigo Izumo; James Hampe; Edward P. Feener

From the Research Division, Joslin Diabetes Center (H.-C.C., J.L.B., A.C.C., E.P.F.), and Beth Israel Deaconess Medical Center (A.S.P., S.I., J.H.), Harvard Medical School, Boston, Mass.

Correspondence to Edward P. Feener, PhD, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail Edward.Feener{at}joslin.harvard.edu

Abstract—Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT₁) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT₁ antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg²-Phe⁸ (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT₁ antagonist candesartan. Angiotensin Val³-Phe⁸ (Ang IV) and angiotensin Asp¹-Pro⁷ (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (P<0.01), and this response was completely blocked by AT₁ receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17- and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (P<0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (P<0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT₁ receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression.

Key Words: angiotensin II • plasminogen activator inhibitor • hypertension • aorta • vascular smooth muscle cells

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